Macular edema is the most common cause of visual loss among patients with uveitis. Although there are multiple approaches to the treatment of uveitis macular edema, no comparative trials of these treatments have been performed. The goal of this proposal is to address two critical issues in the treatment of uveitis macular edema: 1) the optimal initial treatment for uveitis macular edema; and 2) the optimal treatment of persistent macular edema (i.e. macular edema that has not resolved after initial treatment). Regional corticosteroid injections are the mainstay of treatment for uveitis macular edema. However, there are different routes and formulations, which never have been compared in a trial, and the lack of definitive trials has led to considerable variability in clinical practice. or persistent macular edema, repeat injections of corticosteroids typically are administered. However, pilot studies of intravitreal methotrexate and of intravitreal ranibizumab (Lucentis) have suggested efficacy, possibly with fewer ocular side effects than corticosteroid injections, although in the case of ranibizumab possibly with more frequent injections. No comparative trials have been performed of these approaches. The existing MUST Research Group infrastructure will be leveraged to perform two comparative effectiveness clinical trials on the treatment of uveitis macular edema. The specific aims of the trials are: 1) to compare the relative effectiveness of periocular triamcinolone acetonide, intravitreal triamcinolone acetonide (Triescence), and the intravitreal dexamethasone implant (Ozurdex) for the treatment of uveitis macular edema; and 2) to compare the relative effectiveness of intravitreal ranibizumab (Lucentis) and intravitreal methotrexate to the intravitreal dexamethasone implant (Ozurdex) for the treatment of uveitis macular edema that persists after intravitreal triamcinolone injections. The results of these trials will guide clinicians regarding the best approaches for management of uveitis macular edema. The MUST Research Group is uniquely suited to address these issues based upon both its breadth of expertise and proven track record, demonstrated by the successful completion of the MUST Trial and by the ongoing MUST Follow-up Study of participants in the MUST Trial. RELEVANCE: Uveitis is associated with high rates of visual loss, typically caused by structural complications, of which uveitis macular edema is among the most common. Furthermore, macular edema is the most frequent cause of visual loss among patients with uveitis. The two proposed comparative effectiveness trials will provide an evidence base to guide clinicians in the management of uveitis macular edema.